Hypertrophic cardiomyopathy (HCM) is a genetic disease in which the heart muscle (myocardium) becomes abnormally thick (hypertrophied). This thickening of the muscle can make it harder for the heart to relax and pump blood efficiently. Hypertrophic cardiomyopathy may also affect the heart's electrical system resulting in arrhythmias. HCM is the most common genetic cardiac disease, affecting approximately 1 in 500 people. It is caused by autosomal-dominant mutations in genes encoding components of the cardiac sarcomere. HCM is recognized clinically as unexplained left ventricular (LV) hypertrophy (typically ≧15 mm thickness of the ventricular wall) in the absence of other cardiac or systemic conditions capable of producing the magnitude of hypertrophy observed. Typical symptoms include shortness of breath, angina, palpitations, fatigue and syncope. In a small percentage of patients, sudden cardiac death may be the first presentation. HCM is a leading cause of sudden cardiac death in young adults.
There are currently no approved drugs for the treatment of HCM. Empirical medical therapy is considered first-line and is based on using drugs that decrease cardiac contractility including for example, beta-blockers, calcium channel blockers and disopyramide, but their use is limited by lack of efficacy and/or poor tolerability.
Coppini et al. have established a key role for the cardiac late sodium current (INa,L) in the pathogenesis of HCM. In a study of human cardiac tissue derived from patients with symptomatic HCM undergoing septal myectomy (see Coppini et al, Circulation 2013; 127 (5):575-584), inhibition of late INa with ranolazine was found to reverse multiple electrical and mechanical abnormalities characteristic of the disease.
One example of an inhibitor of INa,L is RANEXA®, a compound approved by the FDA for the treatment of chronic stable angina pectoris. RANEXA® has also been shown to be useful for the treatment of a variety of cardiovascular diseases, including ischemia-reperfusion injury, arrhythmia and unstable angina, and also for the treatment of diabetes. It would be desirable to provide compounds and methods for treating HCM via selectively inhibit (INaL) in mammals and that have a similar or improved selectivity over peak INa inhibition of the cardiac sodium channel as compared with RANEXA®.